Beyond CD30: Dual-Targeting of Malignant and Regulatory T Cells by Brentuximab Vedotin Remodels the Lymphoma Microenvironment and Overcomes Resistance via BCL2 Inhibition in Mycosis Fungoides.

Mycosis fungoides (MF), the most common subtype of cutaneous T cell lymphoma (CTCL), has a poor prognosis in advanced stages. Brentuximab vedotin (BV), a CD30-targeting antigen-drug conjugate approved for CD30⁺ MF following prior systemic treatment, still exhibits resistance with unclarified mechanisms. With single-cell RNA analysis on 13 paired tumor samples from 6 CD30⁺ MF patients, we revealed that BV-induced immunogenic cell death (ICD) in both CD30⁺ and CD30⁻ malignant T cells while specifically enhanced interferon-α (IFNα) and IFNγ responses in CD30⁻ subsets. BV also directly targeted CD30⁺ tumor-infiltrating regulatory T cells (TI-Tregs), and activated anti-tumor immunity mediated by dendritic cells and CD8⁺ T cells. The treatment responses and mechanistic insights were validated using seven CTCL cell lines. Resistance arose from upregulated drug efflux transporters and impaired endosomal processing in CD30⁺ malignant T cells, while CD30⁻ tumor cells showed blunted IFNα and IFNγ responses. Anti-apoptotic BCL2 was upregulated in all tumor cells from nonresponsive lesions, especially in CD30⁻ subsets. We further confirmed a potent synergy between BV and BCL2 inhibitors in tumor cell lines, indicating a promising strategy to overcome resistance in CTCL.